Oxygen is required as substrate for more than 100 mammalian enzymes. Little investigation has been made of the functional oxygen dependence of most of these, and therefore, the importance of oxygen-dependent changes in function during hypoxia is not known. This proposal is to examine the oxygen dependence of oxidases involved in drug metabolism and steroidogenesis in order to determine whether decreased function of these enzymes during hypoxia may be important in the pathological manifestations of oxygen deficiency and its medical treatment. The oxygen dependence of drug metabolism by the cytochrome P-450 system and by formation of sulfate conjugates and glucuronic acid conjugates will be studied in isolated rat hepatocytes. The results of these studies will provide information on the degree of hypoxia that causes deficient metabolism of drugs and will therefore indicate conditions in which dosage must be adjusted in response to hypoxia. Steroidogenesis will be studied in isolated adrenocortical cells and subcellular fractions, and in isolated human placental cells. The former was chosen because of previous indications of adrenocortical insufficiency during hypoxia and because the oxygen dependence of key enzymes in this pathway are not known. The latter system was selected because an oxygen deficiency that causes diminished estrogen synthesis near term could be important in premature induction of labor. Preliminary indications are that the enzyme responsible for formation of the aromatic system in estrogen, aromatase, has a very poor affinity for oxygen and might be very sensitive to oxygen deficiency under physiological conditions.